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Fig. 3 | BMC Biology

Fig. 3

From: Lipid metabolism fattens up hedgehog signaling

Fig. 3

Cholesterol homeostasis is maintained by a highly interconnected network of cellular processes. The transcription factor sterol regulatory element-binding protein 2 (SREBP2) positively regulates the expression of cholesterol biosynthetic enzymes. Rising cholesterol levels reduce the rate of cholesterol biosynthesis by modulating the activities of insulin-induced gene (INSIG) proteins. When activated, INSIG both promotes the ubiquitination and consequent destabilization of key metabolic enzymes and inhibits the transcriptional activity of SREBP2 by retaining it in complex with sterol regulatory element-binding protein cleavage-activating protein (SCAP) in the endoplasmic reticulum (ER). Rising cholesterol levels also allosterically activate acyl-coenzyme A:cholesterol acyltransferase (ACAT), which esterifies cholesterol leading to its sequestration in cytosolic lipid droplets. Oxysterol products of cholesterol activate liver-X receptor (LXR) transcription factors, which positively regulate the transcription of proteins that drive cholesterol efflux from the cell (ABCA1 and ABCG1), and sequester it in lipoprotein particles in the circulatory system (ApoE). Activation of oxysterol binding proteins (OSBP) by oxysterols negatively regulates cholesterol efflux by promoting ABCA1 ubiquitination and degradation. Lipoprotein-derived cholesterol is internalized in endosomes that contain Niemann-Pick C1 (NPC1) and NPC2, which act together to redistribute cholesterol to the ER. NPC1 and NPC2 are also critical for the egress of endogenously synthesized cholesterol from endosomes

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